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Lynch Syndrome

Hereditary Non-Polyposis Colon Cancer Type 1

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations of mismatch repair genes. It also the most common etiology of hereditary colorectal and endometrial cancer.


Besides colorectal and endometrial cancer, LS predisposes to malignancies of the small intestine, stomach, pancreas, biliary tract, ovary, upper urinary tract, brain, and skin [1]. Accordingly, the clinical presentation of LS patients may vary largely. Patients suffering from colorectal cancer may experience abdominal pain, altered bowel habits including diarrhea or constipation, or hematochezia. Females with endometrial cancer may describe similar symptoms or may present with abnormal vaginal bleeding or recurrent urinary symptoms. Any type of cancer may eventually provoke constitutional symptoms such as fever, night sweats, and weight loss.

In general, symptoms are non-specific and do not allow for conclusions to be drawn as to the etiology of the disease.

  • During chemotherapy, mild gastrointestinal (nausea, vomiting, diarrhea) and hematological toxicity was observed and the patient experienced for a short period of time fatigue, asthenia, muscle weakness, numbness in limbs.[medichub.ro]
Constitutional Symptom
  • Any type of cancer may eventually provoke constitutional symptoms such as fever, night sweats, and weight loss. In general, symptoms are non-specific and do not allow for conclusions to be drawn as to the etiology of the disease.[symptoma.com]
Abdominal Pain
  • Since then, the patient presented multiple times to the emergency department with severe diffuse abdominal pain.[ncbi.nlm.nih.gov]
  • We present the case of a 68-year-old male with a confirmed diagnosis of Lynch syndrome secondary to a germline MSH2 mismatch-repair gene-mutation who presented with 2 months history of non-specific abdominal pain.[ncbi.nlm.nih.gov]
  • Besides the symptoms associated with the presence of tumors (e.g. colorectal bleeding, weakness, abdominal pain etc.) no other symptoms are described among those with Lynch Syndrome. How is Lynch syndrome diagnosed? By a genetic test.[news-medical.net]
  • It is important that women are aware of the symptoms of endometrial and ovarian cancer and seek advice if they experience unusual vaginal bleeding or discharge or abdominal pain, discomfort or bloating.[genomicseducation.hee.nhs.uk]
  • Patients suffering from colorectal cancer may experience abdominal pain, altered bowel habits including diarrhea or constipation, or hematochezia.[symptoma.com]
  • I suffered tremendously from my oophorectomy; I became severely depressed, suffered from nausea, frequent vomiting, migraines, and severe lethargy for the first couple of years after my surgery.[beseengetscreened.com]
  • During chemotherapy, mild gastrointestinal (nausea, vomiting, diarrhea) and hematological toxicity was observed and the patient experienced for a short period of time fatigue, asthenia, muscle weakness, numbness in limbs.[medichub.ro]
  • […] incontinence, and female genital problems such as protracted labour, dysmenorrhoea, and dyspareunia), local neurological symptoms (sacral anaesthesia, lower extremity paraesthesias, disturbance of anal sphincter control), or central neurological symptoms (nausea[jmg.bmj.com]
  • This patient was a 42-year-old woman with a history of endometrial cancer who had undergone colonoscopy for hematochezia. A 15-mm transverse tubular adenoma was found that was deficient in MLH1 and PMS2.[ncbi.nlm.nih.gov]
  • Patients suffering from colorectal cancer may experience abdominal pain, altered bowel habits including diarrhea or constipation, or hematochezia.[symptoma.com]
Pelvic Mass
  • She presented 12 years later with a pelvic mass and was diagnosed with a high-grade serous primary peritoneal cancer. Genetic testing showed a mutation in the MSH2 DNA mismatch repair gene.[ncbi.nlm.nih.gov]
Severe Abdominal Pain
  • A 49-year-old male patient, morbidly obese, with a background of Lynch syndrome and subtotal colectomy for colon cancer in 2007, presented with severe abdominal pain in December 2015.[ncbi.nlm.nih.gov]
  • Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles.[ncbi.nlm.nih.gov]
Narrow Forehead
  • Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles.[ncbi.nlm.nih.gov]
  • Examinations via radiological imaging were challenging due to body habitus and claustrophobia. In September 2017, the patient was admitted from outpatient clinic with severe abdominal pain, weight loss and anaemia.[ncbi.nlm.nih.gov]


The identification of LS families is based on the Amsterdam criteria and Bethesda guidelines.

While the Amsterdam I criteria aimed at recognizing LS-associated colorectal cancer and did not consider other malignancies associated with this syndrome, the Amsterdam II criteria compensate for this restriction and support the suspicion of LS if the following conditions are met:

  • Histological confirmation of LS-related malignancy in the index case and at least two relatives, with at least one of them being a first-degree relative
  • Involvement of at least two successive generations
  • Diagnosis of early-onset cancer, i.e., at least one of the patients being aged <50 years at the time of the diagnosis
  • Exclusion of familial adenomatous polyposis

The Amsterdam II criteria are highly specific but lack sensitivity; testing according to the Bethesda guidelines yields more sensitive but less specific results. The revised Bethesda guidelines comprise the following criteria:

  • Early-onset colorectal cancer in the index case
  • Colorectal cancer in the index case and early-onset colorectal cancer or another LS-related malignancy in at least one first-degree relative (patient aged <50 years)
  • Colorectal cancer in the index case and colorectal cancer or another LS-related malignancy in at least two first or second-degree relatives (patients of any age)
  • Presence of synchronous or metachronous colorectal cancer or other LS-related malignancies
  • Features of high microsatellite instability in colorectal cancer as observed in a patient aged <60 years (Crohn-like lymphocytic reaction, mucinous or signet-ring cell differentiation, medullary growth pattern)

The diagnosis is ultimately confirmed by the presence of a pathogenic germline mutation of mismatch repair genes, and irrespective of the aforementioned criteria, the current standard of care is to test all specimens of colorectal cancer for mutations implying LS. The same approach is recommended for cases of endometrial cancer. It should be kept in mind that the mere presence of biallelic mutations of mismatch repair genes in cancer cells is no unequivocal sign of LS, and neither is high-level microsatellite instability, since these features may be acquired and thus be confirmed in cancers unrelated to LS. Germline testing is mandatory [2].


Causal treatment is not available. LS patients may be enrolled in surveillance programs as described below, but cancerogenesis cannot yet be prevented.

Surgery and chemotherapy have long since been the mainstays of non-specific cancer treatment in LS patients. In this line, monotherapy with 5-fluorouracil has most frequently been chosen for the treatment of non-metastatic colorectal cancer. Advanced stages of the disease require the administration of combined systemic therapy, e.g., folinic acid, 5-fluorouracil, and oxaliplatin in the FOLFOX regimen, or capecitabine plus oxaliplatin according to the CAPOX protocol [1]. As for the resection of LS-related colon cancer, full colectomy with ileorectal anastomosis is recommended since there's a high risk of metachronous cancers. Other tumors are managed as in the general population.

The presence of mismatch repair deficiencies confers a unique phenotype to LS-related cancers, leading to microsatellite instability and rendering tumor cells particularly susceptible to immune-based therapies. LS patients may thus benefit from recent advances in the use of immune checkpoint inhibitors, which have been proven to be exquisitely effective in the treatment of refractory and/or metastatic malignancies, generating both encouraging and durable responses [2]. In this context, pembrolizumab may be used as an antibody that blocks the interaction between PD-1 on T-cells and the respective ligands expressed by tumor cells. Patients may also receive nivolumab, another antibody targeting PD-1, plus ipilimumab, an antibody against cytotoxic T-lymphocyte antigen 4 [1]. Atezolizumab, which is also directed against PD-1, is currently tested regarding its efficacy when combined with the FOLFOX chemotherapeutic regimen [2].

The same mechanisms that account for the immunogenicity of tumor cells in LS patients may pave the way towards the development of a preventive cancer vaccine for this syndrome. The underlying mutations may give rise to the generation of frameshift peptides, which are recognized as neoantigens by tumor-infiltrating lymphocytes. Accordingly, vaccination with these antigens may represent a promising approach for the treatment and prevention of LS-associated cancers [3].

Interestingly, the daily use of aspirin may reduce the risk of colorectal cancer in LS patients [4].


Microsatellite instability, a characteristic feature of malignancies developing in the setting of LS, has been described as a favorable prognostic factor in cancer patients. This is likely due to the fact that microsatellite instability and the resulting expression of neoantigens allow for an effective immune response against the tumor [5]. Notwithstanding, the diagnosis of LS is associated with a reduction in life expectancy, with about half of cancer-related deaths occurring due to colorectal malignancies [6] [7].


LS may be caused by mutations of distinct genes required for mismatch repair. In detail, alterations of genes PMS2, MSH6, MLH1, and MSH2 have been related to the disease. They are listed here in the order of their assumed prevalence in the general population, which does not coincide with their frequency in cases of hereditary colorectal and endometrial cancer: These malignancies are more often associated with mutations of MLH1 and MSH2 [8]. This apparent discrepancy may likely be explained by differences in the penetrance of these gene defects, a hypothesis that is supported by the fact that founder mutations of the less penetrant genes coincide with lower rates of LS-related hereditary cancers. Such is the case in Iceland, where founder mutations of MSH6 and PMS2 have been identified [9]. The national prevalence of LS is relatively high in Iceland, yet rather few patients are diagnosed with hereditary colorectal or endometrial cancer [2].


The overall prevalence of LS may be as high as 1 in 300 inhabitants [8]. This cancer predisposition syndrome accounts for about 3 and 2% of cases of colorectal and endometrial cancer, respectively [2].

LS patients' lifetime risk of developing colorectal or endometrial cancer ranges between 20-70 and 15-70%, respectively, while the lifetime risks for other LS-associated malignancies are <15%. Most patients are diagnosed with cancer during their fifth or sixth decade of life [1].

Sex distribution
Age distribution


Mutations of mismatch repair genes that underlie LS result in deficiencies of mismatch repair proteins. The possible consequences of such deficiencies have mainly been studied with regard to the development of colorectal cancer, and two hypotheses have been formulated to this end.

According to one of the hypotheses, LS patients may initially develop colorectal polyps in a sporadic manner, similar to any individual who is not carrying LS-associated mutations. Deficiencies of mismatch repair proteins are of minor significance during these early stages of tumorigenesis, but their prevalence increases with the size of adenomatous polyps. This finding has been explained by a second-hit mechanism, where the biallelic loss of gene function confers a phenotypic trait during the later stages of tumor growth. While "healthy" carriers are monoallelic for LS-related mutations and may not even be deficient for mismatch repair proteins, it's the acquired mutation of the second allele that finally accelerates the progression to invasive cancer [10].

On the other hand, the presence of numerous crypt foci lacking mismatch repair proteins in the large intestine of cancer-free LS patients argues in favor of direct cancerogenesis. The cells' inherent inability to recognize and repair DNA damage paves the way for the accumulation of additional gene defects, e.g., somatic mutations of TP53 or CTNNB1 [2].


Prophylactic measures as described in this paragraph aim at the reduction of morbidity and mortality due to LS-associated malignancies, and no recommendations can be given to prevent or even delay the onset of neoplasms.

  • The identification of carriers of relevant predisposition alleles is the basis of LS monitoring. Once identified, LS patients can be enrolled in surveillance programs, most of which focus on the early detection of colorectal cancer.
  • Unfortunately, the optimum interval for surveillance colonoscopies and other diagnostic procedures remains unknown. While some recommend annual screenings to be realized from the age of 25 years, others point out the sufficiency of biannual examinations from the age of 30 years. What's more, a significant proportion of LS-related colorectal cancers continue to be diagnosed in between the scheduled colonoscopies, and it has been suggested that no reduction in colorectal cancer incidence or difference in the stage of detection is achieved by any of the current surveillance programs [11].
  • Regular sonography, hysteroscopy, and/or biopsy may help to detect endometrial cancer and premalignant pathological abnormalities, and women should also be informed about the prospects and possible consequences of risk-reducing hysterectomy and bilateral salpingo-oophorectomy. Still, not all studies show benefits of gynecological surveillance in the early detection of endometrial cancer [12].
  • Furthermore, patients may benefit from upper gastrointestinal endoscopy being carried out every 3-5 years. This is particularly true if there is a family history of gastric or duodenal cancer [11].

In general, the efficacy of current surveillance programs requires improvement. Such might be achieved if the scope of surveillance was adapted to the pathogenicity of the underlying mutation and the corresponding risk for colorectal, endometrial, and other types of cancer. Indeed, genotype-specific recommendations have been published recently: While mutations of MLH1 and MSH2 may warrant more frequent colonoscopies from the age of 25 years, biannual examinations from the age of 30 seem appropriate for those with mutated MSH6 or PMS2. Females carrying MSH2 mutations should undergo gynecological screenings from the age of 30, while non-truncating mutations of MLH1 might allow for surveillance to be delayed until the age of 35. Whereas truncating mutations of MLH1 and pathogenic variants of MSH6 have been shown to justify gynecological surveillance from the age of 40, PMS2 mutations are associated with a very low risk of gynecological cancer, indicating no need for specific monitoring [13]. More comprehensive studies are required to confirm and refine these conclusions.


LS is a cancer predisposition syndrome. Gene defects affecting the mismatch repair system result in mismatch repair deficiencies and microsatellite instability, which largely facilitate the accumulation of other mutations. Carriers of LS-associated mutations have particularly high lifetime risks of developing colorectal and, in the case of female patients, endometrial cancer. Malignancies may also develop elsewhere in the digestive or urogenital tract, in the brain or skin.

This complex condition requires tailored surveillance programs in order to facilitate the early recognition of tumors and to reduce cancer-related morbidity and mortality, but reliable data regarding the efficacy of distinct approaches remain scarce. Much hope has been placed in the development of a vaccine, and research is undergoing to turn this idea into reality. The vaccination against LS-related cancers seems feasible thanks to the immunogenicity of the respective tumor cells, which is also explored in therapeutic settings.

Patient Information

Lynch syndrome (LS) is a hereditary condition predisposing to the development of colorectal, endometrial, and other types of cancer. Carriers of mutations associated with LS have a high lifetime risk of these malignancies, which are often diagnosed at a relatively young age. Additionally, LS patients usually have a family history of early-onset cancer and/or the aforementioned types of cancer.

To date, it is not feasible to prevent the onset of LS-related cancer. Individuals at risk may, however, be included in surveillance programs that facilitate the early detection of abnormalities, which may improve the outcome. The enrolment of carriers is based on a thorough familial workup, where the identification of a single LS patient is followed by the genetic testing of their relatives. What's more, precise knowledge regarding the underlying mutation allows for the individual adaptation of surveillance and an increase in the patient's life expectancy.



  1. Duraturo F, Liccardo R, De Rosa M, Izzo P. Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges. Oncol Lett. 2019; 17(3):3048-3054.
  2. Biller LH, Syngal S, Yurgelun MB. Recent advances in Lynch syndrome. Fam Cancer. 2019; 18(2):211-219.
  3. von Knebel Doeberitz M, Kloor M. Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer. 2013; 12(2):307-312.
  4. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011; 378(9809):2081-2087.
  5. Cohen SA, Pritchard CC, Jarvik GP. Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology. Annu Rev Genomics Hum Genet. 2019.
  6. Evans DG, Ingham SL. Reduced life expectancy seen in hereditary diseases which predispose to early-onset tumors. Appl Clin Genet. 2013; 6:53-61.
  7. de Jong AE, Hendriks YM, Kleibeuker JH, et al. Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology. 2006; 130(3):665-671.
  8. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev. 2017; 26(3):404-412.
  9. Haraldsdottir S, Rafnar T, Frankel WL, et al. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun. 2017; 8:14755.
  10. Yurgelun MB, Goel A, Hornick JL, et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila). 2012; 5(4):574-582.
  11. Jain A, Shafer L, Rothenmund H, et al. Suboptimal Adherence in Clinical Practice to Guidelines Recommendation to Screen for Lynch Syndrome. Dig Dis Sci. 2019.
  12. Crosbie EJ, Ryan NAJ, Arends MJ, et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med. 2019.
  13. Ryan NAJ, Morris J, Green K, et al. Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome: Implications for Stratified Surveillance Strategies. JAMA Oncol. 2017; 3(12):1702-1706.

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Last updated: 2019-07-11 21:58